Abstract
Tissue inhibitor of metalloproteinase 3 (TIMP3) is a protease with high expression levels in the heart and plays an essential role in extracellular matrix turnover by maintaining equilibrium with matrix metalloproteinases. Considerable data in experimental models have demonstrated a protective role of TIMP3 in coronary artery disease (CAD) and myocardial infarction (MI). However, causality remains unexplored in population studies. Here, we sought to decipher the potential causality between TIMP3 and CAD/MI using the Mendelian randomization (MR) method. We extracted summary-level datasets for TIMP3 and CAD/MI from the genome-wide association studies performed in the KORA study and CARDIoGRAMplusC4D consortium, respectively. Seven independent SNPs were obtained as instrumental variables for TIMP3. The MR analyses were replicated using FinnGen datasets, and the main results were combined in meta-analyses. Elevated genetically predicted serum TIMP3 levels were causally associated with a lower risk of CAD [odds ratio (OR), 0.97; 95% confidence interval (CI), 0.95, 0.98; p = 5.29 × 10(-5)] and MI (OR, 0.96; 95% CI, 0.95, 0.98; p = 3.85 × 10(-5)). The association patterns persisted in the meta-analyses combining the different datasets (CAD: OR, 0.97; 95% CI, 0.96, 0.99; p = 4.37 × 10(-5); MI: OR, 0.97; 95% CI, 0.96, 0.99; p = 9.96 × 10(-5)) and was broadly consistent across a set of complementary analyses. Evidence of heterogeneity and horizontal pleiotropy was limited for all associations considered. In conclusion, this MR study supports inverse causal associations between serum TIMP3 and the risk of CAD and MI. Strategies for raising TIMP3 levels may offer new avenues for the prevention strategies of atherosclerotic cardiovascular diseases.